Barium sulphate, a widely used contrast agent for the imaging of the gastrointestinal tract over the years has been administered orally or rectally to millions of patients around the world. Relatively inexpensive, with negligible adsorption and speedy elimination from the body, barium sulphate, despite of its disadvantages, is still in use. Of unpleasant taste, poor adhesion to the luminal linings and insuficient homogeneity in the presence of gastric fluids, this contrast agent has been in use for almost 40 years since proposed alternatives, although off-setting some disadvantages, have not been able to provide GI tract contrast agent which will eliminate use of this otherwise not harmless chemical.
Due to their capacity to efficiently absorb X-rays, and thus generate very good contrasts, iodinated compounds have also been in use in X-ray imaging of gastrointestinal tract. So far, many proposals aiming at improved characteristics of formulations comprising these compounds have been made. Different formulations with lower toxicity, smoother passage through the GI tract, reduced number of undesired side effects, lower irritation of the intestinal mucosa, etc. have been suggested (see for example U.S. Pat. No. 3,360,436, U.S. Pat. No. 4,735,795 & U.S. Pat. No. 5,047,228).
Among different proposals, EP-A-0 436 316 (Sovak) discloses use of hydroxy amino-substituted triiodobenzoates with the remaining position substituted by amino or carboxy group. The compounds disclosed have low solubility in the GI tract and can be formulated and used as contrast agents for radiography of the GI tract. Addition polymers comprised of triiodo compounds bonded through an amino nitrogen to a non-oxo-carbonyl group have been proposed as compounds with low toxicity and improved osmolality vis-a-vis the tract. Compounds and polymers disclosed are obtained by O- or N- alkylation of sodium diatriazoate or triiodobenzoates to yield intermediates which are subsequently polymerized to produce polymers with the molecular weight of at least 50 kDaltons. In the sole example of acylation reaction, 5-amino-2,4,6-triiodo-isophtalic acid is converted to 5-N-acrylamido derivative by reacting acryloyl chloride with 2,3-dihydroxy-propyl 5-{N-(2,3-dihydroxy-propyl)-acetamido}-2,4,6-triiodo-3-{N-(methyl) carbamoyl}-benzoate in dry N,N-dimethyacetamide. All compounds disclosed are ionic in nature which means that they still have higher osmolality than non-ionic compounds.
Another approach has been disclosed in WO-A-93/10824. This document deals with macromolecular polyamine compounds which contain a number of aromatic iodinated molecules. The disclosure is based on use of polyamine polymers to which aromatic iodinated compounds are attached via a number of reaction routes to yield dendrimers useful for manufacture of injectable X-ray contrast agents. Dendrimers disclosed comprise as the backbone all known dense star polymers, dense star polyamines, starbust polymers, star combed-branched polyamines, etc.
Acylation of triiodophenol or iothalamic acid with methacryloyl or methacrylate derivatives has been described as a viable route to production of radiopaque implant materials. Visible in a non-invasive manner using routine X-ray absorption imaging technique, these materials have attracted certain interest in the recent times. Synthetic routes and different studies of these solid polymeric biomaterials are described by A. Jayakrishnan et al. in Journ. Appl. Polymer Sci. 44 (1992) 743, M. A. B. Kruft et al. Journ. Bio. Mat. Res. 28 (1994) 1259, D. Horak, Biomat. 8 (1987) 142, etc.
Thus over the years various improvements of X-ray contrast agents were made bringing different compositions closer to the desired contrast medium for GI tract examinations. However, none of the media presently available has properties which would make any of them to be a widely acceptable GI tract contrast agent. Ideally, contrast agent for GI tract would have negligible adsorption, speedy elimination from the body and the low cost of barium sulfate, would be easier to swallow (have lower vicosity and better i.e. less unpleasant taste), but would also be able to delineate intestinal wall detail, be inert to gastric pH, provide adequate opacificity and have differential affinity for the gastro-intestinal mucosa.